JOURNAL OF VIROLOGY, Dec. 2006, p. 11827–11832
Copyright © 2006, American Society for Microbiology. All Rights Reserved.
Vol. 80, No. 23
Recombination Patterns in Aphthoviruses Mirror Those Found
in Other Picornaviruses?
Livio Heath,1Eric van der Walt,1Arvind Varsani,2and Darren P. Martin3*
Department of Molecular and Cell Biology, Faculty of Science, University of Cape Town, Rondebosch, 7701, South Africa1;
Electron Microscopy Unit, University of Cape Town, Rondebosch, 7701, South Africa2; and Institute of Infectious Disease
and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Observatory 7925, South Africa3
Received 30 May 2006/Accepted 4 September 2006
Foot-and-mouth disease virus (FMDV) is thought to evolve largely through genetic drift driven by the
inherently error-prone nature of its RNA polymerase. There is, however, increasing evidence that recom-
bination is an important mechanism in the evolution of these and other related picornoviruses. Here, we
use an extensive set of recombination detection methods to identify 86 unique potential recombination
events among 125 publicly available FMDV complete genome sequences. The large number of events
detected between members of different serotypes suggests that horizontal flow of sequences among the
serotypes is relatively common and does not incur severe fitness costs. Interestingly, the distribution of
recombination breakpoints was found to be largely nonrandom. Whereas there are clear breakpoint cold
spots within the structural genes, two statistically significant hot spots precisely separate these from the
nonstructural genes. Very similar breakpoint distributions were found for other picornovirus species in
the genera Enterovirus and Teschovirus. Our results suggest that genome regions encoding the structural
proteins of both FMDV and other picornaviruses are functionally interchangeable modules, supporting
recent proposals that the structural and nonstructural coding regions of the picornaviruses are evolving
largely independently of one another.
Foot-and-mouth disease is a highly contagious viral disease
of cloven-hoofed animals and remains a major animal health
concern affecting agricultural economics worldwide. The
causal agent, Foot-and-mouth disease virus (FMDV), is the
type species of the genus Aphthovirus, which constitutes one of
nine genera within the family Picornaviridae (5). Picornaviruses
are small, nonenveloped icosahedral viruses with positive-
sense single-stranded RNA genomes. Their single open read-
ing frame (ORF) encodes a polyprotein that is cleaved during
a cascade of proteolytic events to yield mature viral proteins
(1). The spatial arrangement of the viral genes is somewhat
polarized, with the regions encoding the structural proteins
(1A, 1B, 1C, and 1D) clustered at the 5? end of the ORF. The
majority of the nonstructural proteins (2A, 2B, 2C, 3A, 3B, 3C,
and 3D) are encoded in the 3? half of the ORF, with the only
exception being the leader protein (L). In FMDV, L is a
papain-like protease responsible for the inhibition of cap-de-
pendent translation through cleavage of the eIF4G translation
initiation factor (3).
The extensive genetic and antigenic diversity observed in
RNA viruses such as FMDV is generally attributed to the
error-prone nature of their replication machinery (4).
FMDV is thought to be evolving largely through genetic
drift but with positive selection contributing substantially to
the fixation of mutations, particularly in the capsid coding
regions (8, 20, 21). However, incongruence between the
inferred phylogenies of individual subgenomic regions sug-
gests that recombination may also play a significant role in
FMDV evolution (7, 32, 34). A number of specific FMDV
recombination events have been described thus far. Whereas a
very few events have involved exchanges of genome sequences
encoding parts of the capsid-coding region (P1), all of the rest
seem to have involved genome regions encoding the nonstruc-
tural proteins (11, 12, 32). In this study, we sought first to
identify the set of unambiguously unique recombination events
detectable in publicly available FMDV full genome sequences
and secondly to determine the distribution of these events
across the FMDV genome. We provide evidence that the P1
regions of both FMDV and picornaviruses in general may be
functionally interchangeable modules that facilitate their pro-
miscuous recombinational exchange within different picorna-
MATERIALS AND METHODS
The complete genome sequences of 125 FMDVs were downloaded from
http://virology.wisc.edu/acp in May 2005 and aligned using ClustalX (31; http:
//darwin.uvigo.es/rdp/heath2006.zip). The FMDV species alignment described by
Palmenberg et al. (26) was used to guide a manual editing process. Amino acid
sequence alignments and known biological features were taken into account to
preserve the biological relevance of the alignment.
Phylogenetic-compatibility analysis was performed using the program
TreeOrderScan in the Simmonic 2005 ver. 1.4 package (28, 29). This software
generates “optimally ordered” rooted neighbor-joining trees (100 bootstrap
replicates; all branches with ?70% support are collapsed) for successive
fragments along an alignment (300 nucleotides [nt] in length at 100-nt inter-
vals). The taxon orders within each tree are then compared with those
generated for all the other 300-nt sequence fragments examined along the
alignment. A compatibility matrix is constructed by counting the minimum
number of tree topology alterations required to convert the taxon ordering in
each tree to that of every other tree. Sequences were assigned to predefined
groups (based on their serotypes) in order to compute the numbers of phy-
* Corresponding author. Mailing address: Institute of Infectious
Disease and Molecular Medicine, Observatory, Cape Town, 7925,
South Africa. Phone: 27-21-406 6366. Fax: 27-21-689 1528. E-mail:
?Published ahead of print on 13 September 2006.
by on February 7, 2008
FIG. 1. (a) Phylogenetic compatibility matrix of 125 FMDVs. To generate this plot, a 300-nucleotide window was moved across the alignment
with 100-nucleotide steps, and at each position, a neighbor-joining tree was constructed. The compatibility of two trees is measured by the number
11828HEATH ET AL. J. VIROL.
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logenetic violations between groups of sequences represented in different
To investigate the extent of recombination within the data set, the aligned
sequences were examined using the Recombination Detection Program
(RDP) (16), GENECONV (25), BOOTSCAN (17), MAXIMUM CHI
SQUARE (22), CHIMAERA (19), and SISTER SCAN (6) recombination
detection methods as implemented in RDP3 (19), available from http:
//darwin.uvigo.es/rdp/rdp.html (for full details of program settings, see http:
//darwin.uvigo.es/rdp/heath2006.zip). The breakpoint positions and recombi-
nant sequence(s) inferred for every detected potential recombination event
(PRE) were manually checked and adjusted where necessary using the ex-
tensive phylogenetic and recombination signal analysis features available in
Once a set of unique PREs was identified (http://darwin.uvigo.es/rdp
/heath2006.zip), a breakpoint map containing the positions of all clearly
identifiable breakpoints was compiled. A breakpoint density plot was then
constructed from this map by moving a 200-nt window 1 nucleotide at a time
along the length of the map. At each window position, all identified break-
points falling within the window were counted, and the number was plotted
at the central window position. Significant clustering of breakpoint positions
within each window was tested by permutation. Globally significant break-
point clusters were identified as those windows within the breakpoint density
plot that contained more breakpoint positions than the maximum found in
more than 95% of 1,000 permuted breakpoint density plots. Locally signifi-
cant breakpoint clusters were identified as those windows at a particular
location within the breakpoint density plot that contained more breakpoint
positions than more than 99% of the windows at the same location in the
1,000 permuted breakpoint density plots (for a detailed description of the
permutation test, see http://darwin.uvigo.es/rdp/heath2006.zip).
RESULTS AND DISCUSSION
The major antigenic determinant of FMDV is 1D. Since
the serotypic relatedness of different isolates is reflected
in the phylogeny of the 1D gene region, it has traditionally
been used in the phylogenetic analysis of FMDV sequences.
However, radically incongruent tree topologies between the
structural and nonstructural coding regions of FMDV iso-
lates has suggested that the 1D phylogeny may not appro-
priately reflect the evolutionary histories of different FMDV
isolates (7, 32, 34). To address this issue, we analyzed the
phylogenetic compatibility of successively generated se-
quence fragments across the complete genome sequences of
125 FMDV isolates. Phylogenetic-compatibility analysis in-
dicated extensive incongruence between different regions of
the genome (Fig. 1). Whereas the phylogenies of the 1A, 1B,
and 1C gene regions are consistent with that of 1D, the
phylogeny of the remainder of the genome is largely irrec-
oncilable with that of the P1 region. Phylogenetic-incompat-
ibility values among different parts of the 3? portion of the
genome are only slightly higher than between different re-
gions of P1, but the phylogeny of the 3? half of the genome
is also substantially incompatible with those of the 5? non-
translated region and the L gene. The incongruence of dif-
ferent parts of the FMDV genome suggests that intertypic
recombination may have played an important role in the
evolution of FMDV.
To detect evidence of individual recombination events
within the FMDV alignment, it was examined using a set of six
recombination detection methods implemented in RDP3 (19).
RDP3 uses a mixture of statistical and phylogenetic methods to
both identify evidence of probable recombination events
within individual sequences and identify a minimal subset of
unique events detectable within an entire alignment. Impor-
tantly, the program specifically avoids overestimating the
amount of recombination in an alignment by identifying mul-
tiple descendants of individual recombination events. Eighty-
six unique PREs among FMDV isolates were detected in this
way (http://darwin.uvigo.es/rdp/heath2006.zip). Included in
these 86 PREs are all 8 that have been previously described (2,
32, 34). Twenty-six of the 38 PREs for which two sequences
closely related to the presumed recombinant’s parental se-
quences were identified are between members of different se-
rotypes. This implies that gene flow among serotypes is rela-
tively common and that it does not necessarily incur severe
fitness costs. Importantly, the results of this analysis are in
close agreement with the phylogenetic-compatibility analysis in
that the distribution of observed breakpoints appears to be
nonrandom (Fig. 1). Whereas there are locally significant
breakpoint cold spots in the 1B, 1C, and 1D genes of the P1
region (Fig. 1), the entire P1 region is bounded by two globally
significant (P ? 0.01) breakpoint hot spots.
The results of these FMDV breakpoint distribution and
phylogenetic-compatibility analyses mirror those recently re-
ported for the enteroviruses, another picornavirus genus. Phy-
logenies of the structural and nonstructural genes of enterovi-
ruses are apparently also largely incompatible with one
another (14, 24, 29). This suggested to us that a common
mechanism may be influencing intertype recombination occur-
ring among both aphthoviruses and enteroviruses and that
evidence of the same mechanism might also be detectable in
other picornavirus genera. To test this hypothesis, complete
genome sequences of species A, B, and C enteroviruses (29)
(n ? 28, 61, and 51, respectively) and teschoviruses (27) (n ?
29) were subjected to the same set of analyses as that used on
the FMDV alignment. There are insufficient full genome se-
quences available for members of the other picornavirus gen-
era for analysis of these to have yielded any meaningful results.
We detected evidence of 32, 119, 58, and 46 independent PREs
in the enterovirus species A, B, and C and teschovirus align-
ments, respectively (http://darwin.uvigo.es/rdp/heath2006.zip).
Consistent with previous reports, significant recombina-
tion hot spots were detected at the boundaries of the P1
regions of all three enterovirus species (24, 29). These re-
of phylogenetic violations that are required to match the ordering of taxa within the tree. Obtained values are color coded, with phylogenetically
compatible regions shown in blue. The FMDV genome diagram superimposed on the diagonal axis was drawn to scale relative to FMDV
A10/Holland/62 (AY539751). (b) Potential recombination breakpoint hot spots within the FMDV alignment. Detectable breakpoint positions are
indicated by small vertical lines at the top of the graph. A 200-nucleotide window was moved along the alignment 1 nucleotide at a time, and the
breakpoints detected within the window region were counted and plotted (solid line). The upper and lower broken lines, respectively, indicate 99%
and 95% confidence thresholds for globally significant breakpoint clusters. The light- and dark-gray areas, respectively, indicate local 99% and 95%
breakpoint-clustering thresholds, taking into account local regional differences in sequence diversity that influence the abilities of different methods
to detect recombination breakpoints (for a detailed description of the permutation test, see http://darwin.uvigo.es/rdp/heath2006.zip).
VOL. 80, 2006 RECOMBINATION IN APHTHOVIRUSES11829
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FIG. 2. Phylogenetic-compatibility matrices and breakpoint density plots of enteroviruses and teschoviruses constructed as outlined for Fig. 1.
(a) Enterovirus species A. (b) Enterovirus species B. (c) Enterovirus species C. (d) Teschoviruses. The superimposed genome diagrams were drawn
11830 HEATH ET AL.J. VIROL.
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combination hot spots are most clearly defined in the polio-
virus and nonpoliovirus species C enteroviruses (Fig. 2c),
for which two globally significant breakpoint hot spots are
evident at or close to the boundaries of the P1 region. For
the species A and B enteroviruses, globally significant hot
spots are located close to the 5? boundary of the P1 region
(Fig. 2a and b). Athough there are breakpoint clusters close
to the 3? P1 boundary in both species A and B enterovirus
genomes, the significance of these clusters is not statistically
supported. A locally significant breakpoint hot spot is, how-
ever, apparent in both the enterovirus A and B genomes at
the boundary between the 2A and 2B ORFs (Fig. 2a and b).
It is perhaps also noteworthy that a nonsignificant break-
point cluster between the 2A and 2B ORFs is also evident in
the enterovirus C genomes (Fig. 2c). The globally significant
(P ? 0.01) breakpoint hot spots at or close to the P1 bound-
aries in the teschoviruses closely resemble those observed in
the FMDV and enterovirus C genomes (Fig. 2d). As with
FMDV, the teschovirus 5? untranslated region also contains
a locally significant breakpoint cluster. The other locally
significant teschovirus breakpoint cluster at the 2C-3AB
ORF interface also seems to correspond with breakpoint
clusters at or near the 2C-3AB ORF interface in the A, B,
and C enteroviruses, with the clusters in enterovirus Bs
being locally significant. Importantly, all of the recombina-
tion hot spots identified by the breakpoint-clustering anal-
yses coincide very closely with the boundaries of genomic
regions with maximum phylogenetic conflict indicated by the
Our study supports recent proposals that the constant
generation of variants possessing different combinations of
structural and nonstructural proteins is an important feature
of enterovirus evolution (13, 15, 24, 29). Moreover, our
work suggests that this reassortment of structural- and non-
structural-protein coding regions has played a similarly sig-
nificant role in the evolution of other picornavirus genera.
Recombination in picornaviruses may be analogous to
component swapping or pseudorecombination that occurs
among viruses with multipartite genomes. Such “pseudo-
pseudorecombination” may be strongly facilitated by the
partitioning of structural and nonstructural genes that is
common in picornavirus genomes. Clustering of structural-
protein genes, for example, will massively increase the prob-
ability that single recombination events will transfer them as
an intact genome module.
Although it is likely that there is a common mechanism
influencing the recombination patterns we have observed in
FMDV and other picornaviruses, it is not immediately obvious
what that mechanism might be. The recombination hot spots
described here could be facilitated by conserved biochemical
and/or folded nucleotide structural features at, for example,
the interfaces between the structural- and nonstructural-pro-
tein coding sequences. There does not, however, appear to be
any correlation between the positions of enterovirus genomic-
RNA secondary structures and favored recombination break-
point positions detected in these viruses (29).
It is also possible that recombination occurs throughout
these genomes at roughly the same rate but that recombi-
nants containing breakpoints outside certain well-defined
genome regions (such as at the interfaces between the struc-
tural and nonstructural genes) are generally less fit than
parental viruses. Evaluation of the replicative abilities of
recombinant FMDV and poliovirus genomes provides some
experimental support for the notion that many newly formed
recombinant picornaviruses, if not the vast majority, are
substantially less viable than either of their parents (23, 30,
33). We and others have previously demonstrated that se-
lection seems to favor the survival of recombinants in which
the regions of sequence inherited from different sources
either work well together or do not encode proteins that
interact extensively with one another (10, 18). The viability
of a newly formed recombinant genome is apparently in-
versely correlated with both the complexity of interactions
between genome regions inherited from its different parents
and the relatedness of those parents to one another (10, 18).
It is conceivable that picornavirus recombinants with com-
plexly interacting ORFs inherited from divergent parents
will be removed by purifying selection. If this is true, what
should remain is evidence of a set of recombination events
that accurately anticipate protein-protein, protein-RNA,
and RNA-RNA interactions between viral components. The
apparent paucity of recombination breakpoints within P1
observed in all five picornavirus data sets that we examined
may, for example, indicate that breakpoints occurring in this
region have a high probability of disrupting complex inter-
actions between the various structural proteins that play
crucial roles in the stability and maturation of picornavirus
The results presented here should be of considerable use in
future analyses of picornavirus evolution. Partitioning picorna-
virus genomes at the recombination hot spots we have identi-
fied should both increase the power of and decrease the rate of
false-positive inferences in population-genetic and selection
studies. Our RDP project files (http://darwin.uvigo.es/rdp
/heath2006.zip) can also be directly used with the program
RDP3 to obtain mostly recombination-free picornavirus data
sets that should be of great use in such studies. Besides this, the
files, when loaded into RDP3, are essentially a highly interac-
tive database of probable aphthovirus, enterovirus, and tescho-
virus recombination. These project files will enable detailed
analyses of how, when, and where any of the many individual
PREs detected in this study may have occurred.
to scale relative to sequences NC001430, NC001472, NC002058, and AJ011380. The upper and lower broken lines in each breakpoint density
graph, respectively, indicate 99% and 95% confidence thresholds for globally significant breakpoint clusters. The light- and dark-gray areas,
respectively, indicate local 99% and 95% breakpoint-clustering thresholds, taking into account regional differences in sequence diversity that
influence the abilities of different methods to detect recombination breakpoints (http://darwin.uvigo.es/rdp/heath2006.zip). It should be noted that
apart from a different color scale, the phylogenetic-compatibility analyses presented in panels a, b, and c are a repeat of those, using the same
datasets, previously described by Simmonds and Welch (29) and are included here for comparative purposes.
VOL. 80, 2006 RECOMBINATION IN APHTHOVIRUSES11831
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ACKNOWLEDGMENTS Download full-text
We thank Peter Simmonds for helpful comments on the manuscript.
We thank the Harry Oppenheimer Trust, South African National
Bioinformatics Network, and National Research Foundation for fund-
ing this work. D.P.M. is supported by the Sydney Brenner Fellowship.
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